Isometheptene is a non-ergot vasoconstrictor agent that has been used in the treatment of tension headache, vascular headache and migraine headache either alone or as one or more than one active ingredients in various combination drug products (CDPs) (Horton, B T, Petes, G A and Blumenthal, L S. A new product in the treatment of migraine: A preliminary report, Proc. Staff Meet Mayo Clin. 1945.xx:241-248; Palmer, H. Toxicity of methylamino-iso-octene. Migraine headache, Clinics. 1945. Iv: 531-554; Walton, R P and Preacher, C B, Federation Proc. 1946. v, 211; MacNeal, P. S., and Davis, D.: The Use of methyl-iso-octenylamine in migraine. Ann Intern Med. 1947 26(4):526-7. PMID:20292892; Pantalone A L and Thomas G J. Methyl-iso-octenylamine (octin) relief of headache following spinal tap. Curr Res Anesth Analg. 1952 31(1):69-71. PMID:14896702; Peters G A and Zeller W W. Evaluation of a new agent (methyl-iso-octenylamine) in the treatment of vasodilating headaches. Proc Staff Meet Mayo Clin. 1949 24(23):565-8. PMID:15396281; Seltzer, A.: The use of methyl-iso-octenylamine (Octin) in migraine and related headaches: preliminary report. Med Ann Dist Columbia. 1948 17(7):395-6. PMID: 18871972; Blumenthal, S., and Fuchs, M.: Headache Clinics I. Am. Pract. and Digest Treat. 1950. 10: 1012; Headache Clinics II. Am. Pract. and Digest Treat. 1951. 2:163; Ogden, H D., Headache Statistics II. Headache Patterns. J. Allergy. 1952 23:458; Headache Clinics IV. Am. Pract. and Digest Treat. 1953. 4:31; Brazeau, P.: Oxytocics, in Goodman L. S., Gilman, A. (eds): The Pharmacological Basis of Therapeutics, ed 4. New York, The Macmillan Co. 1970. 893-907; Ogden, H. D.: Controlled studies of a new agent in vascular headache. Headache. 1963 3:29-31. PMID:13939581; Young, H.: A study of a non-ergotamine agent in the office treatment of vascular headache. Ind Med. Surg. 1966 35(2):127-9. PMID:5323440; Johnson, D. E.: An alternative to ergotamines in the treatment of vascular headaches. Clin. Med. 1970. 77:33-36; Yuill, G. M., et al. A double-blind crossover trial of Isometheptene mucate compound and ergotamine in migraine. Br J Clin Pract. 1972 26(2):76-9. PMID:4552744; Diamond, S. Treatment of migraine with Isometheptene, acetaminophen, and dichloralphenazone combination: A double-blind, crossover trial. Headache. 1976 15(4):282-7. PMID:1107267; Valdivia, L F. Pharmacological analysis of the mechanisms involved in the tachycardic and vasopressor responses to the antimigraine agent, Isometheptene, in pithed rats. Life Sciences 2004. 74:3223-3234; Freitag, F G. Comparative Study of a Combination of Isometheptene Mucate, Dichloralphenazone With Acetaminophen and Sumatriptan Succinate in the Treatment of Migraine Headache. 2001 41(4):391-8. PMID:11318886; Gibbs T S. Health Care Utilization in Patients With Migraine: Demographics and Patterns of Care in the Ambulatory Setting Headache. 2003 43(4):330-5. PMID:12656703; Loder, E. Fixed Drug Combinations for the Acute Treatment of Migraine Place in Therapy CNS Drugs. 2005; 19(9):769-84. PMID:16142992; de Souza C D, et al. Efficacy and tolerability of combined dipyrone, Isometheptene and caffeine in the treatment of mild-to-moderate primary headache episodes. Expert Rev Neurother. 2012. 12(2):159-67. doi: 10.1586/ern.11.193. PMID: 22288671).
Isometheptene (6-methylamino-2-methylheptene) was first prepared according to the process described in U.S. Pat. No. 2,230,753 (1941); and it is soluble in water in its hydrochloride or mucate salt form. “Isometheptene is a specified stimulant listed by the World Anti-doping Agency (WADA)” Br. J. Pharmacol. 2008 June; 154(3):606-622.
More particularly, racemic Isometheptene is a well-known aliphatic amine and includes its pharmacologically acceptable acid addition salts (i.e., 2:1 ratio of Isometheptene:mucate). It is a commercially available drug in its common racemic form as a combination drug product (CDP) with acetaminophen (APAP) and dichloralphenazone (DCP) or as a combination drug product with APAP and caffeine. In Brazil, and other countries particularly in South America, Isometheptene is available in combination with dipyrone (de Souza, C D, et al. Efficacy and tolerability of combined dipyrone, Isometheptene and caffeine in the treatment of mild-to-moderate primary headache episodes. Expert Rev Neurother. 2012 12(2):159-67. doi: 10.1586/ern.11.193. PMID: 22288671). It was available in Germany, among several European countries, under the trademark OCTIN from Knoll A. G. (now part of Abbott).
It is believed to be a cerebrovascular constrictor which action may reduce pressure on the pain producing areas surrounding blood vessels. Isometheptene is usually used in combination with other headache ameliorating drugs such as APAP, caffeine and/or dichloralphenazone.
Accordingly, the compositions containing Isometheptene and other active ingredients useful in this invention may be administered either intravenously, parenterally, orally, transdermally, transmucosally, or as a nasal spray. Isometheptene (6-methylamino-2-methylheptene) was first prepared according to the process described in U.S. Pat. No. 2,230,753 (1941); and it is soluble in water in its hydrochloride or mucate salt form. “Isometheptene is a specified stimulant listed by the World Anti-doping Agency (WADA)” Br. J. Pharmacol. 2008 June; 154(3):606-622.
More particularly, racemic Isometheptene is a well-known aliphatic amine and includes its pharmacologically acceptable acid addition salts (i.e., 2:1 ratio of Isometheptene:mucate). It is a commercially available drug in its common racemic form as a combination drug product (CDP) with acetaminophen (APAP) and dichloralphenazone (DCP) or as a combination drug product with APAP and caffeine. In Brazil, and other countries particularly in South America, Isometheptene is available in combination with dipyrone (de Souza, C D, et al. Efficacy and tolerability of combined dipyrone, Isometheptene and caffeine in the treatment of mild-to-moderate primary headache episodes. Expert Rev Neurother. 2012 12(2):159-67. doi: 10.1586/ern.11.193. PMID: 22288671). It was available in Germany, among several European countries, under the trademark OCTIN from Knoll A. G. (now part of Abbott).
It is believed to be a cerebrovascular constrictor which action may reduce pressure on the pain producing areas surrounding blood vessels. Isometheptene is usually used in combination with other headache ameliorating drugs such as APAP, caffeine and/or dichloralphenazone.
In the US, the IDA and ICA products are marketed as prescription drugs under the auspices of the Drug Efficacy Study Implementation (DESI), because they were available before the 1962 FDA reform (1938-1962), were evaluated by National Academy of Sciences/National Research Council to conduct Drug Efficacy Study and were deemed effective for tension and vascular headache and possibly effective for migraine headache.
One DESI ICA product marketed as MigraTen® contained:
It is believed to be a cerebrovascular constrictor which action may reduce pressure on the pain producing areas surrounding blood vessels. Isometheptene is usually used in combination with other headache ameliorating drugs such as APAP, caffeine and/or dichloralphenazone.
Accordingly, the compositions containing Isometheptene and other active ingredients useful in this invention may be administered either intravenously, parenterally, orally, transdermally, transmucosally, or as a nasal spray.
For example, the Isometheptene mucate is commonly administered as a mucate salt in a combination drug product (CDP) containing Isometheptene, dichloralphenazone (DCP), and acetaminophen (APAP) in which the combination product can be abbreviated IDA (IDA) or a different CDP containing Isometheptene, caffeine, and acetaminophen (APAP), which combination product can be abbreviated ICA (ICA).
In the US, the IDA and ICA products are marketed as prescription drugs under the auspices of the Drug Efficacy Study Implementation (DESI), because they were available before the 1962 FDA reform (1938-1962), were evaluated by National Academy of Sciences/National Research Council to conduct Drug Efficacy Study and were deemed effective for tension and vascular headache and possibly effective for migraine headache.
One DESI ICA product marketed as MigraTen® contained: Isometheptene mucate (65 mg); Caffeine (100 mg): acetaminophen (APAP) (325 mg) in a capsule formulation and was deemed possibly effective for relief of migraine headache in a regimen: 2 capsules at once; 1 capsule q1h (up to 5 caps/12 h period) and deemed effective for the relief of tension headache or vascular headache in a regimen of 1-2 capsules q4 h (up to 8 caps/day). Another ICA DESI product on the market is branded as Prodrin® and contains 130 mg of Isometheptene, 20 mg of caffeine, 500 mg of APAP in a tablet formulation with the same dosing instructions for migraine, tension and vascular headache as MigraTen.
One of the DESI IDA products marketed under the trademark Midrin®, contains Isometheptene Mucate (65 mg); Dichloralphenazone (100 mg) and Acetaminophen (325 mg) and is indicated for relief of migraine headache with a usual adult dosage of two capsules at once followed by one capsule every hour until relieved, administering up to 5 capsules within a twelve hour period. Midrin® is also indicated for relief of tension headache with a usual adult dosage of one or two capsules every four hours up to 8 capsules a day.” While the FDA has recognized that Isometheptene is safe and effective by the standards of DESI, various administrative actions to compel DESI manufacturers to upgrade the status of DESI drugs to the level of NDA drugs have resulted in ending the US Midrin production by Curaco since 2011; however, numerous other manufacturers have continued to manufacture and distribute similar products.
Headache indications include several distinct and overlapping conditions including primary and secondary headaches as described in the International Headache Society (HIS) criteria (“Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society”. Cephalalgia 8 Suppl 7: 1-96. 1988. PMID 3048700.) In addition to the headaches classified by the HIS, headaches include vascular headache, which is not mentioned in the Headache classification of the International Headache Society (IHS), although it is still used by many physicians, the US Food and Drug Administration and certain medical classification systems. In the IHS classification, vascular headaches may be considered a cluster headache, migraine and toxic headache.
Headache may be considered a cluster headache, migraine and toxic headache.
Episodic tension-type headache (ETTH) is a subtype of tension-type headache. Tension-type headaches (TTH) are the most common type of headaches among adults, and as a result of high prevalence, imposes the greatest socioeconomic impact of any primary headache type (Bendtsen, 2011; Crystal, 2010). The pain may render a sufferer unable to attend activities, force them to stay home from work, or impair their ability to function at work. According to Mayo Clinic, tension headaches affect 90% of women and 70% of men. According to Vos et. al, (Vos, 2012) it is the most common form of headache and affects 1.4 B people worldwide, approximately 20.8% of the population and affect women more than men (23% to 18% respectively).
A tension-type headache is classified into subtypes based on how often it occurs: infrequent ETTH (<1 day/month on average), frequent ETTH (1-14 days/month on average), or chronic TTH or CTTH (≧15 days/month on average) (International Headache Society, 2013). An ETTH (infrequent or frequent) may be described as a mild to moderate constant band-like pain, tightness, or pressure around the forehead or back of the head and neck. ETTH may last from 30 minutes to several days. ETTH usually begins gradually, and often occurs in the middle of the day. The severity of a tension headache generally increases significantly with its frequency. Because the symptoms of ETTH overlap with other primary headache types, diagnosis is generally made, not only by inclusion, but also of exclusion of certain symptoms such as nausea, exacerbation by physical exercise and occurrence of both photophobia and phonophobia (Sacco, 2008). Once diagnosed and other conditions are ruled out, the primary goal of treatment for ETTH is acute, abortive therapy (Bendtsen, 2011; Lenaerts, 2009), such as would be provided with TNX-201.hronic TTH occurs more frequently, has been shown to be more refractory to successful treatment, and shares many characteristics of a group of headaches called Chronic Daily Headaches or CDH, including sometimes no more than one additional symptom of nausea, photophobia, or phonophobia (Crystal, 2010; International Headache Society, 2013). As a result, accurate diagnosis is imperative, and the primary goal of treatment is headache prophylaxis, including selected anti-depressants, serotonin-specific reuptake inhibitors, benzodiazepines, other anxiolytics, and muscle relaxants (Bendtsen, 2011; Lenaerts, 2009).
Although the mechanism of action for any headache treatment is not yet fully understood, much work has been performed and analysis published. For example, several review articles (Solomon 1995, Gallagher 2002, Gibbs 2003, Mehrota 2008) provide information on the potential pharmacological mechanism of the medications that treat or prevent migraine.
Migraine is described as a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia.
Migraine without aura often has a strict menstrual relationship. In contrast to the first edition of The International Classification of Headache Disorders, the second edition gives criteria for A1.1.1 Pure menstrual migraine, and A1.1.2 Menstrually-related migraine, but lists these conditions in the appendix because of uncertainty over whether they should be regarded as separate entities.
Migraine pathophysiology is believed by genetic predisposition to involve leakage of ion channels in the brain stem such that the decreased blood flow in the brain leads to neuropeptide release from trigeminal nerves inducing dilatation of cranial extracerebral blood vessel. This condition stimulates the trigeminovascular system producing headache associated phonophobia and photophobia as well as nausea and vomiting. A. Maassen VanDenBrink and K. Y. Chan (2008) European J. Pharmacology, 585; 313-319.
Migraine affects people of all races and both sexes with women accounting for 79% (61% between 20 and 49 years of age) of physician visits for migraines and Caucasians for 91% of the physician visits. The pathogenesis of migraine headache involves a) the cranial blood vessels, b) the trigeminal innervation of these vessels, and c) the reflex connection of the trigeminovascular system in the cranial parasympathetic outflow.
In addition to Isometheptene, medications for treating headache that are approved by the Food and Drug Administration (FDA) include as single agents or in combination; acetaminophen (APAP), aspirin (ASA), caffeine, barbiturates (e.g., butalbital), non-steroidal anti-inflammatory drugs (NSAIDS) (e.g., diclofenac), ergot alkaloids (e.g. ergotamine, dihydroergotamine), triptans (e.g., sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, and avitriptan), anti-epileptics (e.g. topiramate) and toxins (ie, botulinum toxin). Some drugs that have been used for headache include neuroleptics (e.g., thorazine, haloperidol). Potential pharmacological targets for the treatment of migraine include medications that target 5-hydroxytryptamine (5-HT) or serotonin receptor subtypes (5-HT1-7), adrenergic receptor subtypes (α1, α2, and β), calcitonin gene-related peptide (CGRP1 and CGRP2) receptors, adenosine (A1, A2, and A3) receptors, glutamate (NMDA, AMPA, kainate, and metabotropic) receptors, dopamine receptors, endothelin receptors, and female hormone (estrogen and progesterone) receptors, plus some miscellaneous receptors and ion channels. The anti-migraine pharmacological mechanism of action of Isometheptene is unknown, but Isometheptene is considered to be a sympathomimetic action leading to cranial vasoconstriction. As described above, Isometheptene mucate is formulated combined in Midrin with acetaminophen and dichloralphenazone (a mild non-barbiturate sedative) wherein Isometheptene is known as sympathomimetic agent acting as both an alpha and beta adrenoreceptor agonist and a vasoconstrictor. If two capsules are taken near the onset of a mild migraine attack followed within an hour by two or three capsules, the treatment consisting of may be satisfactory. Although well tolerated, the dosage is usually not given more than two or three times a week.
Cramps are unpleasant, sometimes painful sensations caused by involuntary muscle contraction or muscle over-shortening. Cramps can be symptoms of muscle spasm. Cramps can be separated into smooth muscle cramps and skeletal muscle cramps. Cramps related to internal (or visceral) organs are related to spasm of smooth muscle or skeletal muscle or distension of organs by functional or pathological disorders. Cramps of internal organs can be associated with visceral pain. Smooth muscle cramps are commonly associated with menstruation or visceral disorders including gastrointestinal and urinary disorders. In the female, smooth muscle cramps that are associated with menstruation, are called menstrual cramps and may also occur before and during a female menstrual cycle. Severe or persistent smooth muscle cramps may also be symptomatic of endometriosis or other health problems. Moreover, smooth muscle cramps can be associated with gastrointestinal disorders, including infectious or autoimmune gastroenteritis and functional disorders such as irritable bowel syndrome (IBS). Thus, smooth muscle cramps are associated with visceral pain in many conditions, including interstitial cystitis. An ideal treatment for cramps would have both analgesic and antispastic properties.
Skeletal muscle cramps are associated with muscle fatigue, low sodium, low potassium and certain drugs, including statins. Skeletal muscle cramps also include nocturnal leg cramps which are involuntary muscle contractions that occur during the night or (less commonly) while resting. Nocturnal leg cramps are common in the elderly, teenagers or in women during the late stages of pregnancy, and can vary in intensity from mild to extremely painful.
Menopause
Menopause is an event that typically (but not always) occurs in women that can be defined as the permanent cessation of the primary functions of the ovaries and is functionally evident when there is a termination of periodic shedding of the uterine lining (known as menses).
Hot and Cold Flushes
Hot and cold flushes (or flashes) are unpleasant sensations associated with vascular events. Hot flashes (also known as hot flushes, or night sweats if they happen at night) are a symptom which may have several other causes, but which is often caused by the changing hormone levels that are characteristic of menopause.
Cognitive Disorders
Cognitive disorders are a category of mental health disorders that primarily affect learning, memory, perception, and problem solving, and include amnesia, dementia, and delirium. Causes vary between the different types of disorders but most include damage to the memory portions of the brain. Mild cognitive impairment (MCI, also known as incipient dementia, or isolated memory impairment) is a brain function syndrome involving the onset and evolution of cognitive impairments beyond those expected based on the age and education of the individual, but which are not significant enough to interfere with their daily activities. MCI can be a transitional stage between normal aging and dementia. Alzheimer's disease (AD) is the most common form of dementia. AD is commonly diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In the early stages, the most common symptom is difficulty in remembering recent events. As the disease advances, symptoms can include confusion, irritability and aggression, mood swings, trouble with language, and long-term memory loss. In later stages, AD patients often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death.
Traumatic Brain Injury
Traumatic brain injury (TBI), also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area). Head injury usually refers to TBI, but is a broader category because it can involve damage to structures other than the brain, such as the scalp and skull.
Neurotoxicity
Neurotoxicity: Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies, certain drug abuse, and organ transplants, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction.
Depression
Anti-depressant, clinical depression, major depression, unipolar depression, unipolar disorder or recurrent depression in the case of repeated episodes) is a psychiatric diagnosis for a mood disorder characterized by episodes of all-encompassing low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities (anhedonia) and disturbed sleep (typically early morning awakening). MDD is a syndrome described by a cluster of symptoms in the American Psychiatric Association's diagnostic manual, DSM-IV. The term “depression” is ambiguous and can be used to describe MDD, but is also used to describe other mood disorders or to lower mood states lacking clinical significance. Bipolar disorder or bipolar affective disorder (historically known as manic-depressive disorder or manic depression) is a psychiatric diagnosis for a mood disorder characterized by episodes of a frenzied state known as mania (or hypomania), typically alternating with episodes of depression described in DSM-IV.
Schizophrenia
Schizophrenia is a psychiatric diagnosis for a thought disorder characterized by a breakdown of thought processes and by a deficit of typical emotional responses. Common symptoms include auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking.
Anxiety
Anxiety disorder is a blanket term covering several different forms of a type of common psychiatric disorder characterized by excessive rumination, worrying, uneasiness, apprehension and fear about future uncertainties either based on real or imagined events, which may affect both physical and psychological health.
Epilepsy
Epilepsy is a common and diverse set of chronic neurological disorders characterized by seizures. In many cases a cause cannot be identified; however, factors that are associated include brain trauma, strokes, brain cancer, and drug and alcohol misuse among others.
Stress Disorders
Stress disorders are an increasingly recognized group of conditions relating to the body's reaction to stressful circumstances and in some cases to decompensated reactions. “Hypothalamic hypophysiotropic factors” were proposed by G. W. Harris in the 1940s and substantial body of evidence has confirmed that these factors may contribute to stress disorders (Chrousos, G. P. Stress and disorders of the stress system Nat. Rev. Endocrinol. 5, 374-381 (2009); published online 2 Jun. 2009; doi:10.1038/nrendo.2009.106; Raisman, G. An urge to explain the incomprehensible: Geoffrey Harris and the discovery of the neural control of the pituitary gland. Ann. Rev. Neurosci. 1997: 20:533-566; Chrousos, G. P. & Gold, P. W. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. JAMA 1992: 267:1244-1252. Charmandari, e., Tsigos, C. & Chrousos, G. P. Neuroendocrinology of stress. Ann. Rev. Physiol. 2005. 67: 259-284.)
Excess Sweating
Hyperhidrosis or excess sweating, can either be generalized or localized to specific parts of the body. Hands, feet, armpits, and the groin area are among the most active regions of perspiration due to the relatively high concentration of sweat glands. When excessive sweating is localized it is referred to as primary or focal hyperhidrosis. Generalized or secondary hyperhidrosis usually involves the body as a whole and is the result of an underlying condition. Hyperhidrosis can also be classified depending by onset, either congenital or acquired. Primary or focal hyperhidrosis must be distinguished from secondary hyperhidrosis, which can start at any point in life. The later form may be due to a disorder of the thyroid or pituitary glands, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning. Hyperhidrosis may also be divided into palmoplantar (symptomatic sweating of primarily the hands or feet), gustatory and generalized hyperhidrosis.
Symptoms Related to Drug Withdrawal
Withdrawal is the group of symptoms that occur upon the abrupt discontinuation or decrease in intake of medications or recreational drugs. In order to experience the symptoms of withdrawal, one must have first developed a physical or mental dependence (often referred to as chemical dependency). Withdrawal happens after consuming one or more substances for a certain period of time, which is both dose dependent and varies based upon the drug consumed.
In view of these various aspects of migraine a wide variety of prospective targets for migraine treatment exists.
As is presently understood, sympathomimetic drugs activate the sympathetic nervous system and mimic the effect of catecholamine substances that act directly as agonists of one or more receptors that include alpha (α1, α2) and beta (β) adrenergic receptors. Natural endogenous catecholamines include dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Of these catecholamine (or monoamine) substances, dopamine and norepinephrine are generally considered neurotransmitters, and adrenaline is generally considered a hormone, but these distinctions are vague in practice. Generally, sympathomimetic drugs act in several direct or indirect ways including: causing the release of catecholamines from synapses; inhibiting the reuptake of inhibiting the reuptake of catecholamines from synapses; inhibiting the metabolism or degradation of catcholamines; interacting with adrenergic receptors directly as agonists; and/or modulating the sensitivity or responsiveness of catecholamine responsive cells or systems.
Isometheptene has been shown to increase heart rate and diastolic blood pressure, which are properties associated with sympathomimetic agents. The heart rate increase has been shown to be blocked by propranolol, a non-selective beta (β) adrenergic receptor antagonist, while the diastolic blood pressure increase has been shown to be blocked by prazosin, an alpha-1 (α1) adrenergic receptor antagonist. Valdivia, L. F., Cenurion, D., Perusquia, M., Arulmani, U., Saxena, P. R., and Villalom, C. M. “Pharmacological Analysis of the Mechanisms Involved in the Tachycardic and Vasopressor Responses to the Antimigraine Agent, Isometheptene, in Pithed Rats” Life Sciences 74: 3223-3234 (2004). Together these findings suggest that racemic Isometheptene has sympathetic effects which are complex on heart rate and blood pressure. However, it is unknown whether Isometheptene interacts with alpha (α)- or beta (β)-adrenergic receptors as an agonist, and/or stimulates the release of catecholamines, and/or modulates the sensitivity of catecholamine responsive cells or systems.
Some comparisons have been made of the pressor effects of Isometheptene and those of tyramine (4-hydroxyphenethylamine; para-tyramine, mydrial or uteramin). Tyramine is a naturally occurring monoamine compound that acts as a catecholamine releasing agent. Tyramine is present in a plants and animals. But high levels of tyramine are typically found in the diet from the metabolism of microorganisms (decarboxylation of tyrosine) in cheese or wine. In humans, tyramine is metabolized by monoamine oxidase (MAO) and if MAO function is inhibited by the use of monoamine oxidase inhibitors (MAOIs), then dietary tyramine can raise blood pressure and in rare cases, precipitate a hypertensive crisis, which is also referred to as the “cheese effect”. Tyramine may act on a group of G protein-coupled receptors, such as TA1 or TAAR1 that is expressed in brain as well as peripheral tissues, including the kidneys.
A literature search was conducted to obtain information on nonclinical pharmacology and safety (safety pharmacology, pharmacokinetic, and toxicology) of Isometheptene alone and in a CDP to support an IND on Isometheptene. The results of this literature search indicated that 35 papers that reference Isometheptene have been published since 1972. Upon review of the abstracts of these published papers, 12 of these 35 papers provided some information on the mechanism of action of Isometheptene for the treatment of migraine, the pharmacological profile of Isometheptene in animal models, and the pharmacokinetics and metabolism of Isometheptene in animals and humans. None of these publications provide information on the toxicological profile of Isometheptene in animals.    Moffett, Adrienne; Swash, M; Scott, D F (1972). “Effect of tyramine in migraine: a double-blind study”. Journal of Neurology, Neurosurgery, & Psychiatry with Practical Neurology 35, 4: 496-499. doi:10.1136/jnnp.35.4.496.    D'Andrea, G; Nordera, G P; Perini, F; Allais, G; Granella, F (May 2007). “Biochemistry of neuromodulation in primary headaches: focus on anomalies of tyrosine metabolism”. Neurological Sciences 28, Supplement 2: S94-S96. doi:10.1007/s10072-007-0758-4. PMID 17508188.    Borowsky B, Adham N, Jones K A, Raddatz R, Artymyshyn R, Ogozalek K L, Durkin M M, Lakhlani P P, Bonini J A, Pathirana S, et al. (2001). “Trace amines: identification of a family of mammalian G protein-coupled receptors.” Proc Natl Acad Sci USA 98:8966-8971.
Imidazoline-I1 Receptors:
A receptor system that modulates sympathetic effects has been recently identified and termed the imidazoline receptors (I receptors). Three isoforms have been identified: I1, I2, and I3. A putative natural ligand is agmatine (see below).
Moxonidine is believed to be an agonist of the I1 receptor and the net effect of moxonidine is sympathoinhibitory (Schafer), so that agonists of the I1 receptor generally are sympathoinhibitory and antagonists are sympathomimetic. Schafer U, Burgdorf C, Engelhardt A, Raasch W, Kurz T, Richardt G. Moxonidine displays a presynaptic alpha-2-adrenoceptor-dependent synergistic sympathoinhibitory action at imidazoline-I1 receptors. Ann NY Acad Sci 2003; 1009: 265-269.
Clonidine is also a ligand of the I1/moxonidine receptor and is sympathoinhibitory. However, Clonidine is also a centrally acting alpha-2 agonist, which is believed to account for many of its effects on sympathetic tone and on treatment effects. Central alpha-2 receptors are believed to be pre-synaptic and agonists to central alpha-2 receptors decrease sympathetic outflow. Clonidine was developed and initially FDA approved and used for the treatment of hypertension but has since found other uses, including treatment of attention deficit hyperactivity disorder (ADHD) in an extended release form. Off-label uses, supported by less evidence, suggest effects on some types of neuropathic pain, opioid detoxification, sleep hyperhidrosis, anxiety and panic disorder, insomnia, menopausal symptoms and as an anaesthetic drug.
Clonidine is applied in conjunction with stimulants to treat ADHD because it may moderate ADHD-associated impulsive and oppositional behavior, and may reduce tics, which are involuntary movements in ADHD or Tourette syndrome. Clonidine is used to ease sympathetic withdrawal symptoms (tachycardia and hypertension) associated for example with the long-term use of narcotics, alcohol and nicotine (smoking). Moreover, Clonidine is applied to reduce sweating, hot and cold flushes, and general restlessness in drug withdrawal and also menopause.
Clonidine has also been studied to treat pain during heart attack, postoperative and intractable pain as an oral or epidural agent.
Agmatine [(4-aminobutyl)guanidine] is believed to be an endogenous ligand for I1 receptors and to function as an agonist. Agmatine was identified in herring sperm in 1910 by Albrecht Kossel. Kossel, Albrecht 1910. Über das Agmatin. Zeitschaft für Physiologische Chemie 66: 257-261
Agmatine has several properties of neurotransmitters: it is synthesized in the brain, stored in synaptic vesicles, accumulated by uptake, and released by membrane depolarization. Agmatine is the decarboxylation product of the amino acid arginine and inactivated by agmatinase. In addition to I1 receptors, agmatine binds to the α2-adrenergic receptor (where it has neither agonist nor antagonist effect) and blocks NMDA receptors and other cation ligand-gated channels. Functionally, agmatine inhibits nitric oxide synthase (NOS) and induces the release of some peptide hormones.
Exogenous agmatine treatment has been shown in animal studies to exert a variety of activities including: anti-convulsant (Aricioglu, F., et al. Effect of agmatine on electrically and chemically induced seizures in mice. Ann. N.Y. Acad. Sci., 2003. 1009:141-146), antineurotoxic (Halaris, A., Piletz, J. Agmatine: metabolic pathway and spectrum of activity in brain. CNS Drugs, 2007. 21:885-900), vasodilatory (Satriano, J. Agmatine: at the crossroads of the arginine pathways. Ann. N.Y. Acad. Sci., 2003. 1009:34-43), neuroprotective (Kuo, J. R., et al. Agmatine promoted angiogenesis, neurogenesis, and inhibition of gliosis-reduced traumatic brain injury in rats. J. Trauma 2011 71(4):E87-93. doi: 10.1097/TA.0b013e31820932e2; Lu W, et al. Agmatine inhibits morphine-induced memory impairment in the mouse step-down inhibitory avoidance task. Pharmacol Biochem Behav 2010; 97:256-61; McKay B E, et al. Learning and memory in agmatine-treated rats. Pharmacol Biochem Behavior 2002; 72:551-7; Zarifkar A, et al. Agmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis. Eur J Pharmacol 2010; 634:134-8; Bhutada, P et al Agmatine, an endogenous ligand of imidazoline receptor protects against memory impairment and biochemical alterations in streptozotocin-induced diabetic rats. Progress in Neuro-Psychopharmacology & Biological Psychiatry 37 (2012) 96-105), anti-apoptotic (Wang, C. C., et al., Beneficial effect of agmatine on brain apoptosis, astrogliosis, and edema after rat transient cerebral ischemia. BMC Pharmacol. 2010. 10:11), anxiolytic (Gong, Z. H., et al. Anxiolytic effect of agmatine in rats and mice. Eur. J. Pharmacol. 2006. 550:112-116), memory enhancing (Arteni N S, et al. Agmatine facilitates memory of an inhibitory avoidance task in adult rats. Neurobiol Learn Mem 2002; 78:465-9.; Liu P and Bergin D H. Differential effects of i.c.v. microinfusion of agmatine on spatial working and reference memory in the rat. Neuroscience 2009; 159:951-61; Liu P and Collie N D. Behavioral effects of agmatine in naive rats are task- and delay dependent. Neuroscience 2009; 163:82-96), antidepressant (Zomkowski, A. D., et al. Agmatine produces antidepressant-like effects in two models of depression in mice. NeuroReport 2002. 13:387-391; Aricioglu, F. and Altunbas, H. Is agmatine an endogenous anxiolytic/antidepressant agent? Ann. N.Y. Acad. Sci. 2003. 1009: 136-140.; Li, Y. F., et al. Antidepressant-like effect of agmatine and its possible mechanism. Eur. J. Pharmacol. 2003. 469:81-88; Halaris and Piletz, 2007 (Ibid.); Taksande, B. G., et al. Antidepressant like effect of selective serotonin reuptake inhibitors involve modulation of imidazoline receptors by agmatine. Neuropharmacology 2009. 57: 415-424), anti-diabetic (Chang C H, et al. Increase of beta-endorphin secretion by agmatine is induced by activation of imidazoline I(2A) receptors in adrenal gland of rats. Neurosci Lett 2010; 468:297-9; Hwang S L, et al. Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats. Diabetologia 2005; 48:767-75; Ozyazgan S, et al. The effect of agmatine on the vascular reactivity in streptozotocin-diabetic rats. Pharmacol Res 2003; 48:133-8) and anti-oxidant (Battaglia V, Grancara S, Satriano J, Saccoccio S, Agostinelli E, Toninello A. Agmatine prevents the Ca(2+)-dependent induction of permeability transition in rat brain mitochondria. Amino Acids 2010; 38:431-7.; Condello S, Curr M, Ferlazzo N, Caccamo D, Satriano J, Ientile R. Agmatine effects on mitochondrial membrane potential and NF-κB activation protect against rotenoneinduced cell damage in human neuronal-like SH-SY5Y cells. J Neurochem 2010; 116:67-75; Demady D R, Jianmongkol S, Vuletich J L, Bender A T, Osawa Y. Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme. Mol Pharmacol 2001; 59:24-9).
Agmatine is metabolized by agmatinase (Mistry S K, et al. Cloning of human agmatinase. An alternate path for polyamine synthesis induced in liver by hepatitis B virus. Am J Physiol Gastrointest Liver Physiol. 2002 282(2):G375-81), which is upregulated in hippocampal interneurons of subjects with mood disorders (Bernstein, H-G et al, Agmatinase, an inactivator of the putative endogenous antidepressant agmatine, is strongly upregulated in hippocampal interneurons of subjects with mood disorders. Neuropharmacology 62 (2012) 237e246).
Agmatinase is an enzyme encoded in human by a gene located on chromosome 1p36, a gene locus which has repeatedly been linked to bipolar disorder and major depression and in some cases to schizophrenia (Fanous A H, et al. Genetic overlap of schizophrenia and bipolar disorder in a high-density linkage survey in the Portuguese Island population. Am J Med Genet B Neuropsychiatr Genet. 2012 159B(4):383-91. doi: 10.1002/ajmg.b.32041. Epub 2012 Mar. 27. PMID:22461138; McGuffin, P., et al. Whole genome linkage scan of recurrent depressive disorder from the depression network study. Hum. Mol. Genet., 2005. 14:3337-3345; Tatemir, D., et al. Chromosomal fragile site expression in Turkish psychiatric patients. Psychiatry Res. 2006. 144:197-203; Demirhan, O., et al. The expression of folate sensitive fragile sites in patients with bipolar disorder. Yonsei Med. J. 2009. 50:137-141; Diagnostic and Statistical Manual of Mental Disorders Revised 1987. DSM IIIR; American Psychiatric Association; Kaneva, R., et al. Bipolar disorder in the Bulgarian Gypsies: genetic heterogeneity in a young founder population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009. 150B:191-201; Fullerton, J. M., et al. Two-dimensional genome scan identifies multiple genetic interactions in bipolar affective disorder. Biol. Psychiatry, 2010. 67:478-486).
Several agonists of the I1 receptor have been identified and studied. Moxonidine and Rilmenidine are considered selective agonists at the imidazoline receptor subtype 1 (I1). Moxonidine and Rilmenidine are prescription medications for the treatment of hypertension outside the U.S. Rilmenidine is marketed under the brand names HYPERIUM, Iterium and Tenaxum. The I1 receptor subtype is found in both the rostral ventro-lateral pressor and ventromedial depressor areas of the medulla oblongata. Moxonidine therefore causes a decrease in sympathetic nervous system activity and, therefore, a decrease in blood pressure. Compared to the older central-acting antihypertensives, moxonidine binds with much greater affinity to the I1-receptor than to the alpha-2-adrenergic receptor. In contrast, clonidine binds to both receptors with equal affinity. Selective I1 agonists may promote sodium excretion, improve insulin resistance and glucose tolerance and protect against hypertensive target organ damage, such as kidney disease and cardiac hypertrophy. However, Moxonidine may be associated with poor outcomes in heart failure (Cohn J et al. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON) Eur J Heart Fail (2003). 5 (5): 659-67. doi:10.1016/S1388-9842(03)00163-6. PMID 14607206.